Antiviral vaccine rebounds versus herpes

Washington - A glycoprotein vaccine has induced significant protection
against genital herpes disease in women with no evidence of either herpes simplex
virus 1 or HSV 2 infection, said Stephen K. Tyring, M.D., Ph.D., at the annual
meeting of the American Academy of Dermatology.

The limitations of current therapies for HSV and human papillomavirus
have engendered research into antiviral vaccines, said Dr. Tyring, professor,
departments of dermatology, microbiology, immunology, and internal medicine,
University of Texas Medical Branch, Galveston, who reviewed the state of
antiviral vaccine development.

Two years ago Dr. Tyring and colleagues reported in The Journal of the
Medical Association (1999;282:331-340) that a glycoprotein vaccine was able
to induce neutralizing antibodies to HSV but did not provide protection
against genital herpes. "This should have been the end of recombinant
glycoprotein vaccines, but it wasn't," Dr. Tyring said. "In the
past few months, we analyzed data from a study that involved a recombinant
glycoprotein D from HSV-2 that was secreted from transfected mammalian cells.
This was put into a different adjuvant than the one used in the study reported
in JAMA." The adjuvant used in the most recent studies of the HSV glycoprotein
vaccine was SBAS4, which contained alum and monophosphoryl lipid A (MPL).
The adjuvant in the earlier study was MF59, a 5 percent squalene oil-in-water
emulsion.

Two double-blind, randomized, placebo-controlled multicenter international
trials were conducted by Dr. Tyring and colleagues with the new vaccine.
Persons without a history of genital herpes but with a partner with recurrent
genital herpes were eligible for the studies. They received the vaccine
or the adjuvant alone at months zero, one, and six, and were followed for
at least 19 months. The primary efficacy endpoint was the incidence of genital
herpes disease, which required the presence of genital herpes signs and
symptoms plus seroconversion.

One study, which enrolled 847 persons, required participants to be negative
for both HSV-1 and HSV-2 at entry. In the second study, 2,491 persons of
unknown HSV status at entry, but no history of disease, were enrolled. The
study participants had been with their current partners for 29 to 37 months
and reported varying histories of condom use.

Studies show ladies first

When the data from the two studies were combined, the incidence of new
herpes disease was not different among the groups who received the vaccine
and the adjuvant only. However, "we saw something very exciting when
we segregated the men from the women; the women were protected but men were
not," Dr. Tyring said. "This has never been reported before in
a study of a prophylactic vaccine."

Women who were negative for both HSV-1 and HSV-2 had statistically significant
protection with the vaccine versus placebo. The vaccine efficacy in women
negative for both HSV-1 and HSV-2 was 73.2 percent (p = 0.01) in the first
study and 74.4 percent (p = 0.02) in the second study.

"Those who were seropositive for HSV-1 had little protection whether
they were men or women," Dr. Tyring said. In women who had HSV-1 antibodies,
the vaccine appeared to boost protection against HSV-2 above the background,
but this finding did not reach significance. "Of course, the women
who are double negative are the ones at most risk," he said.

The vaccine was safe and well-tolerated, with transient and low-grade
fever being the most common side effect, although it was rare. The reason
the vaccine protected women but not men against HSV cannot be answered without
examining IgA in cervical secretions, Dr. Tyring said, which will be part
of the design of future studies.

"This is the first demonstration of a vaccine efficacy against genital
herpes disease," he said. "It is also the first demonstration
of a vaccine that has worked in women and not in men. It appears to be a
very promising candidate for further development. The more potent adjuvant
is the theory why this vaccine worked and other ones didn't, but we really
don't know that."

Hope for HPV vaccine

Integration of viral DNA into the host DNA characterizes HPV that progresses
to malignancy, as with HPV types 16, 18, 31, 33, and 35. "With integration
of viral DNA into the host DNA, there are several steps by which the virally
infected cell goes to dysplasia and neoplasia," Dr. Tyring said. "We've
learned from studying this process that many or most women who are infected
with oncogenic HPV spontaneously clear their viral infections; there is
no viral DNA on the Pap smear and there are antibodies to type 16 or 18.
This gives us a precedent for the development of vaccines, not just for
first-order vaccines to prevent the infection but second-order vaccines
to boost the immune system if they're carrying the virus but haven't developed
dysplasia or neoplasia."

Vaccines are also under study for the nononcogenic form of HPV, he said.
These forms of HPV differ molecularly because they stay in an episomal state
and are eventually packaged and released as infectious virions (common warts).
"In going from a viral infection to dysplasia and neoplasia, we know
that the sub-type is very important; that is, if you have types 16 or 18
you're far more likely to develop an anogenital malignancy than if you have
types 6 or 11," Dr. Tyring said.

Gene expression is also important in the risk for malignancy; upregulation
of certain oncogenes and downregulation of certain anti-oncogenes can predispose
to progression towards malignancy. Co-carcinogens such as cigarette smoking
and helper viruses also play roles in increasing the potential for malignancy.
However, "even if all other known risk factors are controlled for,
there still seems to be a genetic predisposition for a viral infection with
an oncogenic HPV type to proceed to malignancy," Dr. Tyring said. DT